Itching is a sensation, i.e., pruritic sensation, which takes place at the superficial layer of the skin and the mucosa. The pruritic sensation is a sensation, which senses a parasite or an irritant on the superficial layer of the skin and is for removing an invading substance or an irritant by scratching or related behavior. Itching can be easily understood as a sensation to cause an impulse to scratch, but its mechanism has not been elucidated completely yet.
Diseases accompanied by itching are roughly classified into pruritic dermatosis accompanied by skin lesion (for example, atopic dermatitis, urticaria, psoriasis, xeroderma and tinea) and pruritus cutaneous, which is not accompanied by skin lesions, but causes itching due to kidney dialysis and visceral diseases [for example, diabetes, blood diseases, cholestatic liver injury (primary biliary liver cirrhosis) and kidney diseases], hyperthyroidism, multiple sclerosis or the like. In addition, as a disease accompanied by severe itching, diseases of cornea and conjunctiva such as allergic conjunctivitis can be exemplified. Recently, such diseases have rapidly increased to constitute a large problem in view of QOL (quality of life). Most itching diseases are common in the fact that they cause a vicious cycle of scratching the skin. Histamine is known as a typical itch-causing substance and induces itching in the case where it is externally added and is internally released from mastocytes.
An antihistaminic agent, an antiallergic agent, a steroid external preparation and the like are used for the treatment of pruritic dermatosis. However, there is no drug that is satisfactory for the treatment of itching due to pruritic dermatosis. Further, it has recently been reported that factors other than histamine take part in itching due to atopic dermatitis. In fact, also in many clinical cases, an antihistaminic agent or an antiallergic agent does not exert a remarkable effect on itching due to atopic dermatitis. In the treatment of pruritus cutaneous, antihistaminic agents or steroid external preparations are prescribed in some cases. However, almost no effect is seen, and thus an effective therapy does not exist at present. As described above, there is no satisfactory drug for diseases accompanied by itching and a medicament which effectively suppresses itching regardless of causative diseases has been eagerly desired from a clinical point of view.
In order to solve this problem, several antipruritic agents have been identified, including quinazoline derivatives (WO 03/091224), neuronal nitric oxide synthase inhibitors (JP-A-2002-138052), cannabinoid receptor agonists (JP-A-2003-201250), glutamate receptor inhibitors (JP-A-2004-107209), piperidine derivatives (JP-A-2005-047909), prostaglandin derivatives (JP-A-2005-139194) and the like have been reported. Among these, quinazoline derivatives disclosed in WO 03/091224 strongly suppress scratching behavior spontaneously occurring in a mouse model with disruption of the horny layer barrier and is useful as a drug for effectively suppressing itching regardless of causative disease.
The skin of pruritic diseases, especially of atopic dermatitis or the like accompanied by skin lesion develops disruption of the horny layer barrier or hypersensitivity of the sensory nerves in comparison with the normal skin, and the skin is recognized to be sensitive to stimulation. When an external preparation is applied to such pruritic diseases, the external preparation is required to have an extremely low skin irritation. However, when the quinazoline derivative described in WO 03/091224 which has a guanidino group in the side chain at the 4-position of the quinazoline skeleton is used as an external preparation for a patient with atopic dermatitis, there is a possibility of causing skin irritation.